scholarly journals A Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of Biapenem in Healthy Adult Subjects

2021 ◽  
Author(s):  
David C. Griffith ◽  
Elizabeth E. Morgan ◽  
Michael N. Dudley ◽  
Jeffery S. Loutit
Keyword(s):  
Adverse Events ◽  
Healthy Adult ◽  
Phase 1 ◽  
Urinary Recovery ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Multiple Doses ◽  
Dose Study ◽  
Dose Proportional

The pharmacokinetics and safety of biapenem were studied in 36 healthy adult subjects in a randomized, placebo-controlled, double blind, sequential single and multiple-ascending dose study using doses from 250 to 1250 mg administered three times a day using 3-hour infusions. Maximum concentrations for biapenem were achieved at the end of the 3-hour infusion. Biapenem exposure (AUC) increased in a slightly greater than dose-proportional manner following single and multiple doses with no evidence of accumulation with multiple doses. Plasma AUCs increased from 18 mg*h/L at 250 mg to 150 mg*h/L at 1250 mg. Urinary recovery ranged from 14.2% at 250 mg to 42.3% at 1250 mg. Biapenem was well tolerated up to 1000 mg administered every 8 hours by 3-hour infusion for 7 days; however, a higher incidence of nausea, vomiting, and rash was reported at 1250 mg. There were no serious adverse events (SAEs) reported following either single or multiple doses of biapenem and all AEs were mild or moderate in severity.

scholarly journals A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of an Anti-Influenza B Virus Monoclonal Antibody, MHAB5553A, in Healthy Volunteers

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Jeremy J. Lim ◽  
Michael A. Derby ◽  
Yaping Zhang ◽  
Rong Deng ◽  
Richard Larouche ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase 1 ◽  
Influenza B Virus ◽  
Influenza B ◽  
Double Blind ◽  
Double Blind Placebo ◽  
B Virus ◽  
Dose Study ◽  
Single Ascending Dose Study ◽  
Dose Proportional

ABSTRACT Influenza B can cause significant morbidity and mortality. MHAB5553A, a human monoclonal immunoglobulin G1 (IgG1) antibody that binds to a highly conserved region of the hemagglutinin protein of influenza B virus, is being examined as a novel therapeutic for the treatment of influenza B patients with severe disease. This phase 1, randomized, double-blind, placebo-controlled, single-ascending-dose study was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of MHAB5553A. Twenty-six healthy male and female volunteers of >18 years of age were randomized into five cohorts receiving a single intravenous (i.v.) dose of 120, 1,200, 3,600, 8,400, or 10,800 mg MHAB5553A or placebo (four active:one placebo, except for the 120-mg cohort [4:2]). Subjects were followed for 120 days after dosing. No subject discontinued the study, no dose-limiting adverse events or serious adverse events were reported, and a maximum tolerated dose (MTD) was not defined. The most commonly reported adverse events were cold symptoms and headache; most were mild and occurred at a similar rate across all cohorts. MHAB5553A showed no relevant time- or dose-related changes in laboratory values or vital signs compared to the placebo. The observed serum PK was linear and generally dose proportional, and the observed nasal PK was nonlinear and generally non-dose proportional. MHAB5553A is generally well tolerated in healthy volunteers up to at least a single i.v. dose of 10,800 mg and demonstrated linear serum PK consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (This study has been registered at ClinicalTrials.gov under registration no. NCT02528903.)

scholarly journals Human Safety, Tolerability, and Pharmacokinetics of a Novel Broad-Spectrum Oral Antiviral Compound, Molnupiravir, with Activity Against SARS-CoV-2

2020 ◽  
Author(s):  
Wendy P. Painter ◽  
Wayne Holman ◽  
Jim A. Bush ◽  
Firas Almazedi ◽  
Hamzah Malik ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Influenza Viruses ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Antiviral Compound ◽  
Multiple Doses

AbstractMolnupiravir, EIDD-2801/MK-4482, the prodrug of the ribonucleoside analog ß-d-N4-hydroxycytidine (NHC), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, seasonal and pandemic influenza viruses, and respiratory syncytial virus.Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics.EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure.Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.Clinical trial identifierThis study was registered at ClinicalTrials.gov with the identifier NCT04392219.

scholarly journals Human Safety, Tolerability, and Pharmacokinetics of Molnupiravir, a Novel Broad-Spectrum Oral Antiviral Agent with Activity Against SARS-CoV-2

2021 ◽  
Author(s):  
Wendy P. Painter ◽  
Wayne Holman ◽  
Jim A. Bush ◽  
Firas Almazedi ◽  
Hamzah Malik ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Clinical Laboratory ◽  
Phase 1 ◽  
Influenza Viruses ◽  
Controlled Study ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Time Curve ◽  
Multiple Doses

Molnupiravir, EIDD-2801/MK-4482, the prodrug of the active antiviral ribonucleoside analog ß-d-N4-hydroxycytidine (NHC; EIDD-1931), has activity against a number of RNA viruses including severe acute respiratory syndrome coronavirus 2, severe acute respiratory syndrome coronavirus, Middle East respiratory syndrome coronavirus, and seasonal and pandemic influenza viruses. Single and multiple doses of molnupiravir were evaluated in this first-in-human, phase 1, randomized, double-blind, placebo-controlled study in healthy volunteers, which included evaluation of the effect of food on pharmacokinetics. EIDD-1931 appeared rapidly in plasma, with a median time of maximum observed concentration of 1.00 to 1.75 hours, and declined with a geometric half-life of approximately 1 hour, with a slower elimination phase apparent following multiple doses or higher single doses (7.1 hours at the highest dose tested). Mean maximum observed concentration and area under the concentration versus time curve increased in a dose-proportional manner, and there was no accumulation following multiple doses. When administered in a fed state, there was a decrease in the rate of absorption, but no decrease in overall exposure. Molnupiravir was well tolerated. Fewer than half of subjects reported an adverse event, the incidence of adverse events was higher following administration of placebo, and 93.3% of adverse events were mild. One discontinued early due to rash. There were no serious adverse events and there were no clinically significant findings in clinical laboratory, vital signs, or electrocardiography. Plasma exposures exceeded expected efficacious doses based on scaling from animal models; therefore, dose escalations were discontinued before a maximum tolerated dose was reached.

scholarly journals 1288. Phase 1 First-in-Human Single- and Multiple-Ascending Dose Trial Demonstrates Pharmacokinetics (PK) and Tolerability of SPR720, an Oral DNA GyrB Inhibitor for Mycobacterial Infections

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S659-S659
Author(s):  
Angela Talley ◽  
Archie Thurston ◽  
Grayson Moore ◽  
Myriah M Satterfield ◽  
Erika L Manyak ◽  
...  
Keyword(s):  
Adverse Events ◽  
Healthy Volunteers ◽  
Controlled Trial ◽  
Phase 1 ◽  
Safety Data ◽  
Elderly Subjects ◽  
Independent Contractor ◽  
Serious Adverse Events ◽  
Healthy Elderly ◽  
Dose Proportional

Abstract Background SPR720 (phosphate pro-drug of SPR719) is a novel aminobenzimidazole bacterial DNA gyrase (GyrB) inhibitor in development for non-tuberculous mycobacterial lung disease (NTM-LD) and pulmonary tuberculosis. SPR719 has broad-spectrum activity versus clinically relevant mycobacteria in vitro and in murine and hollow fiber (HF) infection models. In this first-in-human single ascending dose (SAD) /multiple ascending dose (MAD) study, the safety, tolerability and pharmacokinetics (PK) of SPR720/SPR719 were evaluated in healthy volunteers. Methods This was a Phase 1 randomized, double-blind, placebo-controlled trial with 7 SAD cohorts (including a food effect cohort) and 5 MAD cohorts. Healthy volunteers (n=8/cohort, 3:1 randomization) received SPR720 or placebo in single oral doses of ranging from 100 mg to 2000 mg or repeat total daily doses ranging from 500 mg to 1500 mg for 7 or 14 days. Safety monitoring and PK sampling occurred throughout the trial. Plasma and urine concentrations of SPR720/SPR719 were measured by validated LC-MS/MS methods. PK parameters were calculated using non-compartmental analysis. Results A total of 96 subjects (including 8 healthy elderly subjects, age ≥ 65 years) were randomized and received study drug. SPR720 was well-tolerated at daily doses up to 1000 mg for up to 14 days. Across SAD/MAD cohorts, the most common adverse events were gastrointestinal (nausea, vomiting and diarrhea) and headache, all of mild or moderate severity and dose dependent. No serious adverse events were reported. Across SAD cohorts, a dose proportional and greater-than-dose proportional increase in SPR719 plasma Cmax and AUC0-24, respectively were observed. SPR720 was rapidly absorbed with a mean SPR719 t1/2 of 2.9-4.5 h. Dosing with food decreased SPR719 plasma AUC by ~20%. No clinically meaningful effect of age on plasma AUC was observed. In the MAD cohorts, SPR719 plasma exposure declined approximately 40% between Day 1 and Day 7, suggesting induction of an elimination pathway. However, plasma AUC0-24 was similar at Days 7 and 14. Conclusion Together with HF pharmacodynamic data, human PK and safety data for SPR720 suggest that predicted therapeutic exposures can be attained with a well-tolerated once-daily dose. Further evaluation in a Phase 2 NTM-LD trial is planned. Disclosures Angela Talley, MD, Spero Therapeutics (Employee, Shareholder) Archie Thurston, Jr., PhD, Spero Therapeutics (Consultant) Grayson Moore, BA, RN, Spero Therapeutics, Inc. (Shareholder, Independent Contractor) Vipul Kumar, PhD, Spero Therapeutics (Employee, Shareholder) Suzanne Stokes, PhD, Spero Therapeutics (Employee, Shareholder) Aaron Dane, MSc, Spero theraputics (Consultant) David Melnick, MD, Spero Therapeutics (Employee)Spero Therapeutics (Employee)

scholarly journals Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus

2021 ◽  
Author(s):  
Sumathi Sivapalasingam ◽  
George A Saviolakis ◽  
Kirsten Kulcsar ◽  
Aya Nakamura ◽  
Thomas Conrad ◽  
...  
Keyword(s):  
Middle East ◽  
Adverse Events ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Preclinical Study ◽  
Middle East Respiratory Syndrome ◽  
Lung Pathology ◽  
Phase 1 Study ◽  
Serious Adverse Events ◽  
Dipeptidyl Peptidase 4

Abstract Background REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. Methods Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. Results Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. Conclusions REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

scholarly journals Phase 1 Study of the Safety, Tolerability, and Pharmacokinetics of the β-Lactamase Inhibitor Vaborbactam (RPX7009) in Healthy Adult Subjects

2016 ◽  
Vol 60 (10) ◽  
pp. 6326-6332 ◽  
Author(s):  
David C. Griffith ◽  
Jeffery S. Loutit ◽  
Elizabeth E. Morgan ◽  
Stephanie Durso ◽  
Michael N. Dudley
Keyword(s):  
Plasma Clearance ◽  
Healthy Adult ◽  
Phase 1 ◽  
High Dose ◽  
Double Blind ◽  
Time Curve ◽  
Content Type ◽  
Multiple Doses ◽  
To Receive ◽  
Lactamase Inhibitor

ABSTRACTVaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, double-blind, sequential single- and multiple-ascending-dose study. A total of 10 dose cohorts were enrolled in the study, with 6 subjects randomized to receive 250 to 2,000 mg of vaborbactam and 2 subjects randomized to receive placebo in each cohort. Maximum concentrations for vaborbactam were achieved at the end of the 3-h infusion. Vaborbactam exposure (Cmaxand area under the concentration-time curve [AUC]) increased in a dose-proportional manner following multiple doses. There was no evidence of accumulation with multiple doses, consistent with the terminal half-life of ∼2 h. Both the volume of distribution (Vss) and plasma clearance were independent of dose. For the 2,000-mg dose, the plasma clearance was 0.17 ± 0.03 liters/h, the AUC from 0 h to infinity (AUC0–∞) was 144.00 ± 13.90 mg · h/liter, and theVsswas 21.80 ± 2.26 mg · h/liter. Urinary recovery was 80% or greater over 48 h across all dose groups. No subjects discontinued the study due to adverse events (AEs), and no serious AEs (SAEs) were observed. All AEs were mild to moderate and similar among the vaborbactam- and placebo-treated subjects, with mild lethargy as the only unique AE reported with the high dose of vaborbactam. Overall, this study revealed the safety, tolerability, and pharmacokinetic profile of vaborbactam and formed the basis for advancement into patient studies in combination with meropenem, including treatment of patients with carbapenem-resistantEnterobacteriaceae(CRE) infections. (This study is registered at ClinicalTrials.gov under identifier NCT01751269.)

scholarly journals Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial

2021 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Boris Julg ◽  
C. Sabrina Tan ◽  
Rebecca Zash ◽  
Stephen R. Walsh ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Adverse Events ◽  
Antiviral Activity ◽  
Controlled Trial ◽  
Phase 1 ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Cell Counts ◽  
Hiv 1

AbstractHuman immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg–1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg–1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

A Phase 1 Study to Evaluate the Safety and Pharmacokinetics following Administration of Single and Multiple Doses of the Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects

2022 ◽  
Author(s):  
Mary Beth Wire ◽  
Soo Youn Jun ◽  
In-Jin Jang ◽  
Seung-Hwan Lee ◽  
Jun Gi Hwang ◽  
...  
Keyword(s):  
Healthy Adult ◽  
Phase 1 ◽  
Infusion Site ◽  
Healthy Male ◽  
C Reactive Protein ◽  
Phase 1 Study ◽  
Reactive Protein ◽  
Male Subjects ◽  
Common Teaes ◽  
Dose Proportional

Thirty-two healthy male subjects (8 per cohort) were randomized 6:2 to active:placebo. LSVT-1701, an anti-staphylococcal lysin, was administered intravenously as a 6 mg/kg single dose and as 1.5, 3, and 4.5 mg/kg twice daily for 4 days. LSVT-1701 exposure increased in a greater than dose proportional manner and did not accumulate. Treatment-emergent adverse events (TEAEs) were predominantly of mild intensity. The most common TEAEs were chills, pyrexia, headache, infusion site events, cough, rhinorrhea, and increases in C-reactive protein.

scholarly journals A Phase 1 Randomized Placebo-Controlled Study to Assess the Safety, Immunogenicity and Genetic Stability of a New Potential Pandemic H7N9 Live Attenuated Influenza Vaccine in Healthy Adults

Vaccines ◽  
2020 ◽  
Vol 8 (2) ◽  
pp. 296
Author(s):  
Irina Kiseleva ◽  
Irina Isakova-Sivak ◽  
Marina Stukova ◽  
Marianna Erofeeva ◽  
Svetlana Donina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Influenza Vaccine ◽  
Phase 1 ◽  
Healthy Adults ◽  
Controlled Study ◽  
Temperature Sensitive ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Human Influenza Virus ◽  
Live Attenuated Influenza Vaccine

This study describes a double-blind randomized placebo-controlled phase I clinical trial in healthy adults of a new potential pandemic H7N9 live attenuated influenza vaccine (LAIV) based on the human influenza virus of Yangtze River Delta hemagglutinin lineage (ClinicalTrials.gov Identifier: NCT03739229). Two doses of H7N9 LAIV or placebo were administered intranasally to 30 and 10 subjects, respectively. The vaccine was well-tolerated and not associated with increased rates of adverse events or with any serious adverse events. Vaccine virus was detected in nasal swabs during the 6 days after vaccination or revaccination. A lower frequency of shedding was observed after the second vaccination. Twenty-five clinical viral isolates obtained after the first and second doses of vaccine retained the temperature-sensitive and cold-adapted phenotypic characteristics of LAIV. There was no confirmed transmission of the vaccine strain from vaccinees to placebo recipients. After the two H7N9 LAIV doses, an immune response was observed in 96.6% of subjects in at least one of the assays conducted.

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